DESCRIPTION: The goal of this FIRST proposal is to develop peptide-shielded oligonucleotides as a means to protect nucleic acid-based therapeutic agents during delivery. The first specific aim is to design chemical syntheses for hybrids between peptides, 5-16 residues and nucleic acids 2-8 nucleotides in length for purposes of improving bioavailability and stability of the oligonucleotides. Three classes of peptides have been chosen: SPKK (histone tails), PRGRP (HMG-I protein DNA binding domain), the KWK motifs (single strand selective) and AAKK repeats (known to increase kinetics of DNA hybridization). Specific aim two is to select peptide-DNA hybrids with increased target affinity and biostability. Specific aims three and four deal with structural studies of DNA-peptide conjugates. UV and CD studies will determine the effect of peptide on thermodynamic stability of DNA single strand and DNA duplex. NMR and x-ray studies of peptide-DNA conjugates are also proposed. A fifth aim of the proposal is to link a third function to the peptide-DNA conjugate that further enhances cellular uptake such as a fusogenic peptide sequence.